Trimethylaminuria results from the abnormal presence of large amounts of volatile and malodorous trimethylamine within the body. This chemical, a tertiary aliphatic amine, is excreted in the urine, sweat (ichthyohidrosis), and breath, which take on the offensive odor ... Trimethylaminuria results from the abnormal presence of large amounts of volatile and malodorous trimethylamine within the body. This chemical, a tertiary aliphatic amine, is excreted in the urine, sweat (ichthyohidrosis), and breath, which take on the offensive odor of decaying fish (Mitchell, 1996).
Individuals with trimethylaminuria excrete relatively large amounts of amino-trimethylamine (TMA) in their urine, sweat, and breath, and exhibit a fishy body odor characteristic of the malodorous free amine, leading to the designation fish-odor syndrome. TMA is a product ... Individuals with trimethylaminuria excrete relatively large amounts of amino-trimethylamine (TMA) in their urine, sweat, and breath, and exhibit a fishy body odor characteristic of the malodorous free amine, leading to the designation fish-odor syndrome. TMA is a product of intestinal bacterial action. The substrates from which it is derived are choline, which, bound to lecithin, is present most abundantly in egg yolk, liver, kidney, legumes, soy beans, and peas, as well as from trimethylamine-N-oxide, a normal constituent of saltwater fishes. Normally, TMA produced in the gut is absorbed and oxidized in the liver by FMO, a microsomal mixed-function oxidase (Higgins et al., 1972). Humbert et al. (1970) first used the terms trimethylaminuria and fish-odor syndrome to describe a 6-year-old girl who intermittently had a fishy odor. She also had multiple pulmonary infections beginning in the neonatal period, the clinical stigmata of Turner syndrome but normal karyotype, splenomegaly, anemia, and neutropenia. Her urine contained increased amounts of TMA. In the same patient, Humbert et al. (1971) found defective membrane function in platelets, neutrophils, and red cells, and Higgins et al. (1972) found deficiency of trimethylamine oxidase by liver biopsy. Calvert (1973) noted that the features in the patient of Humbert et al. (1970) were those of Noonan syndrome (163950). He studied a clinically identical patient but found no trimethylaminuria with or without loading with trimethylamine. Witt et al. (1988) included the patient of Humbert et al. (1970) in their series of cases of Noonan syndrome with bleeding diathesis. Lee et al. (1976) observed a brother and sister with trimethylaminuria; in both, an offensive fishy odor occurred when the mother was breast feeding them and had eaten eggs or fish. Danks et al. (1976) referred to 4 affected individuals in their personal experience. Mayatepek and Kohlmuller (1998) described 2 unrelated children with transient trimethylaminuria. One was a 2-month-old female infant referred because of an offensive odor on her skin and from her urine which was noticed by the parents. When the child was 6 months old, the fishy odor completely disappeared. The second patient was a 4-year-old boy who was referred because of smelly urine and skin which had been noticed by his mother from about the age of 18 months. In these children, transient trimethylaminuria occurred without N-oxidation deficiency. Zschocke et al. (1999) studied patients with mild trimethylaminuria and concluded that FMO3 deficiency is a spectrum of phenotypes that can include transient or mild malodor depending on environmental exposures. Mild FMO3 deficiency may have clinical relevance beyond intermittent body odor leading to an abnormal metabolism of drugs, hypertension, or increased cardiovascular disease risk. Todd (1979) noted that patients with TMA may be deeply disturbed, depressed, and even suicidal, with psychosocial problems in school. Rehman (1999) also reported that patients with TMA often have psychosocial problems, including strong feelings of shame, embarrassment, low self-esteem, social isolation, anxiety, and depression.
Akerman et al. (1997) and Dolphin et al. (1997) demonstrated that trimethylaminuria is caused by mutation in the FMO3 gene (136132). One individual of British extraction was shown to be homozygous for an E305X mutation (136132.0001) of the ... Akerman et al. (1997) and Dolphin et al. (1997) demonstrated that trimethylaminuria is caused by mutation in the FMO3 gene (136132). One individual of British extraction was shown to be homozygous for an E305X mutation (136132.0001) of the FMO3 gene; this person, in addition to trimethylaminuria, had tachycardia and severe hypertension after eating cheese (which contains tyramine) and after using nasal epinephrine following an epistaxis (Danks et al., 1976). The FMO3 enzyme metabolizes tyramine. Zschocke et al. (1999) examined the patients of Mayatepek and Kohlmuller (1998) with transient trimethylaminuria and other patients with mild trimethylaminuria and found compound heterozygosity for a missense mutation on one allele and 2 amino acid polymorphisms (E158K, E308G) on the other allele (see, e.g., 136132.0015). Zschocke et al. (1999) found that the variant allele with the 2 polymorphisms occurred in 20% and 6% of German and Turkish controls, respectively. The authors performed standardized TMA challenge tests in the controls with this variant allele and found markedly reduced FMO3 enzyme activity in vivo.
Trimethylaminuria may present with a body odor resembling that of rotten or decaying fish [Mitchell & Smith 2001, Mitchell 2005, Mackay et al 2011]. ...
DiagnosisClinical DiagnosisTrimethylaminuria may present with a body odor resembling that of rotten or decaying fish [Mitchell & Smith 2001, Mitchell 2005, Mackay et al 2011]. Diagnosis of trimethylaminuria has been discussed in detail [Cashman et al 2003] and "best-practice" diagnostic guidelines have been summarized [Chalmers et al 2006; see ]. Diagnosis based on the sense of smell of the examiner is complicated by the following: The presence of the odor is often episodic and thus may not be noticeable when the person is examined. The human nose is normally very sensitive to trimethylamine, with some individuals being able to detect concentrations as low as 1 part in 109; however, olfactory testing is subjective and some people are unable to detect the smell of trimethylamine. The odor may be caused by compounds other than trimethylamine. TestingMetabolism of trimethylamine is primarily via N-oxygenation, catalyzed by the enzyme flavin-containing monooxygenase 3 (FMO3) [Lang et al 1998, Cashman et al 2003, Phillips et al 2007]. Biochemical testing. Trimethylaminuria is characterized by excretion of excessive amounts of unoxidized trimethylamine in the urine, breath, sweat, and reproductive fluids. Trimethylamine is extremely volatile and has a pungent ammoniacal odor reminiscent of rotting fish [Mitchell 2005, Mackay et al 2011]. Diagnosis of trimethylaminuria is based on one of the following:Percent of total trimethylamine (TMA) (i.e., free TMA plus the non-odorous metabolite TMA N-oxide) excreted in the urine as unmetabolized free TMA [Cashman et al 2003, Mackay et al 2011]. Severe trimethylaminuria: more than 40% of total TMA excreted as unmetabolized free TMA Mild trimethylaminuria: 10%-39% of total TMA excreted as unmetabolized free TMA Unaffected: 0%-9% of total TMA excreted as unmetabolized free TMA Concentration of unmetabolized TMA in the urine. A urinary concentration of free TMA of 10 µg/mL (18-20 µmol/mmol creatinine) or higher, correlating with a urinary output of TMA of about 15 to 20 mg/day, appears to represent a threshold for the presence of the fishy body odor associated with the disorder [Mitchell & Smith 2001]. Note: (1) Some forms of trimethylaminuria are transient or episodic [Mitchell & Smith 2001, Mitchell 2005]; to distinguish them from the primary inherited form, biochemical testing should be performed on two separate occasions. (2) Choline challenge. It may also help to carry out the biochemical testing after an oral challenge of choline bitartrate (2.5 to 15g, depending on age) [Chalmers et al 2006]. Although this level of choline challenge is generally well tolerated, one individual developed an adverse reaction, with fever and vomiting [Chalmers et al 2006]. (3) Because unaffected women may have a short episode of trimethylaminuria at the onset of and during menstruation [Shimizu et al 2007], females should not be tested during this time frame.The methods of detecting TMA and TMA N-oxide in urine currently available involve sophisticated equipment and require skilled and experienced personnel:Head-space gas chromatography (GC) or GC-mass spectrometry [Mills et al 1999]. Disadvantages: GC techniques are time consuming, TMA N-oxide must be chemically reduced to TMA before analysis, and both TMA and TMA produced by reduction of TMA N-oxide must be extracted from urine. Mass spectroscopy (MS)* including fast atom bombardment MS (FAB-MS) [Mamer et al 1999], electrospray ionization tandem MS (ESI-MS/MS) [Johnson 2008], direct infusion electrospray quadruple time-of-flight MS [Mamer et al 2010], or matrix-assisted laser desorption/ionization time-of-flight MS (MALDI-TOFMS) [Hsu et al 2007] Proton nuclear magnetic resonance (NMR) spectroscopy* [Maschke et al 1997, Murphy et al 2000, Podadera et al 2005, Lee et al 2006] * MS and proton NMR have the advantage of being able to detect TMA and TMA N-oxide simultaneously with great sensitivity. NMR has the further advantage of requiring no prior extraction or separation of metabolites and thus measurement can be done directly on urine samples. Heterozygotes Under normal dietary conditions heterozygotes (carriers) and unaffected individuals excrete less than 10% of total TMA as the unmetabolized free amine and thus cannot be distinguished [Cashman et al 2003]. TMA challenge. Carriers can be detected using a "TMA load" test in which 600 mg of TMA is given orally in a gelatin capsule. After the TMA load test, carriers excrete 20%-30% of total TMA as the free unmetabolized amine, whereas unaffected individuals excrete less than 13% of total TMA as the free unmetabolized amine [Mitchell & Smith 2001]. Molecular Genetic TestingGene. FMO3 is the only gene in which mutations are known to cause trimethylaminuria. Clinical testing Sequence analysis. It is estimated that 99% of FMO3 mutations may be detected by sequence analysis. Insufficient studies have been published to establish the mutation detection frequency. Deletion/duplication analysis. Forrest et al [2001] reported a homozygous deletion of exons 1 and 2 in an individual with trimethylaminuria. To date, this is the only FMO3 allele reported with a large deletion.Table 1. Summary of Molecular Genetic Testing Used in TrimethylaminuriaView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityFMO3Sequence analysis Sequence variants 2~99% 3 ClinicalDeletion / duplication analysis 4Exonic or whole-gene deletionsUnknown 1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. Insufficient studies have been published to establish the actual mutation detection frequency. 4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm/establish the diagnosis in a proband. Individuals complaining of or exhibiting a fishy odor should be tested for urinary excretion of TMA, ideally on two separate occasions. Testing can be done under normal dietary conditions or following a choline challenge. Note: The choline challenge described in Testing can help confirm TMA in affected individuals. The choline challenge does not distinguish between carriers and unaffected individuals. If an individual excretes more than 10% of total TMA as the free amine under normal dietary conditions, sequence analysis should be offered.If an individual is found to be homozygous or compound heterozygous for known loss-of-function mutations of FMO3, the diagnosis is confirmed. If novel mutations are found, it is important to establish that: The mutations are not relatively common in the general population, i.e., polymorphic variants; They cosegregate with the disorder in the family; They abolish (or substantially reduce) the ability of FMO3 to catalyze N-oxygenation of TMA, as assessed by assaying heterologously expressed mutant protein. Carrier testing for at-risk relatives. Carriers can be distinguished from unaffected individuals with the TMA challenge described in Testing, Heterozygotes or by molecular genetic testing which requires prior identification of the disease-causing mutations in the family.Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersNo other phenotypes are known to be associated with mutations in FMO3.
Trimethylaminuria is characterized by fishy odor resulting from excess excretion of trimethylamine in the urine, breath, sweat, and reproductive fluids [Mitchell 2005, Mackay et al 2011]. ...
Natural HistoryTrimethylaminuria is characterized by fishy odor resulting from excess excretion of trimethylamine in the urine, breath, sweat, and reproductive fluids [Mitchell 2005, Mackay et al 2011]. The trimethylamine is derived from dietary precursors, such as choline and trimethylamine N-oxide, via the action of bacteria in the gut [Mitchell 2005, Mackay et al 2011]. It is normally metabolized in the liver by the enzyme FMO3 to produce trimethylamine N-oxide, which is non-volatile and non-odorous [Cashman et al 2003, Phillips et al 2007]. Excess trimethylamine results from a mismatch between the ability of the enzyme FMO3 to catalyze the N-oxygenation of trimethylamine and the amount of substrate.Two types of trimethylaminuria exist, resulting from one of the following:Decrease in the amount or activity of the enzyme FMO3, resulting from either genetic factors (mutations in FMO3), physiologic factors (hormone levels), or environmental factors (presence of inhibitory chemicals). This type of trimethylaminuria is characterized by a high urinary TMA/TMA N-oxide ratio. Substrate overload of FMO3 enzyme activity resulting from either an excess of dietary precursors of TMA or variations in gut flora, causing increased release of TMA. This type of trimethylaminuria is characterized by a high concentration of TMA in the urine, but a normal urinary TMA/TMA N-oxide ratio. The two types of trimethylaminuria are intimately interrelated: a combination of genetic, physiologic, and environmental factors may interact to give rise to the disorder. For instance, a substrate load that is handled by one individual may represent a substrate overload for a person whose FMO3 enzyme activity is decreased. No physical symptoms are associated with trimethylaminuria; affected individuals appear normal and healthy. However, the unpleasant odor characteristic of the disorder often results in social and psychological problems [Mitchell & Smith 2001] and can have serious effects on personal and working lives. These may include the following:In childhood, being shunned, ridiculed, or bullied at school, leading to aggressive or disruptive behavior and poor educational performance A sense of shame or embarrassment, leading to low self-esteem and reluctance to seek medical help Avoidance of contact with people, leading to social isolation, loneliness, frustration, and depression Difficulties in initiating or maintaining relationships In extreme cases, paranoid behavior, desperation, and suicidal tendencies The enzyme FMO3 is also involved in the metabolism of various therapeutic drugs. Affected individuals exhibit abnormal metabolism of the nonsteroidal anti-inflammatory benzydamine [Mayatepek et al 2004]. Anecdotal evidence suggests that the metabolism of other drugs that are substrates of the enzyme FMO3 may also be affected. Dysfunctional metabolism of endogenous amines such as tyramine that are substrates of the enzyme FMO3 may contribute to the depression seen in some persons.For individuals with primary genetic trimethylaminuria, symptoms are usually present from birth. The condition may worsen during puberty. In females, symptoms are more severe just before and during menstruation, after taking oral contraceptives, and around menopause, probably because of a decrease in expression of FMO3 in response to steroid hormones.Treatment and dietary management may alleviate symptoms in some, but not all individuals.Other. Historical references to individuals who appear to have had trimethylaminuria include the description of Satyavati, a young woman who smelled of rotting fish, in the Mahabharata, the Indian epic of the Bharata Dynasty compiled in about AD 400, and Trinculo's description of Caliban ("he smells like a fish") in Shakespeare's The Tempest.
A classification scheme for trimethylaminuria has been proposed [Mitchell & Smith 2001, Mitchell 2005]....
Differential DiagnosisA classification scheme for trimethylaminuria has been proposed [Mitchell & Smith 2001, Mitchell 2005].Primary genetic trimethylaminuria. Caused by FMO3 mutations that result in loss of function of FMO3 enzyme activity, this subtype accounts for the majority of reported cases [Phillips et al 2007]. Combinations of certain FMO3 polymorphisms may cause a less severe form of the condition [Zschocke et al 1999]. Acquired trimethylaminuria emerges during adult life as a consequence of hepatitis in individuals with no previous personal history or familial history of the disorder. The metabolic changes persist after the liver problems have resolved, suggesting a permanent change in the expression or activity of the FMO3 enzyme. Transient childhood trimethylaminuria has been reported in preterm infants fed a choline-containing infant formula. Symptoms disappear as the children mature or when the choline source is discontinued [Pardini & Sapien 2003]. Young children who are heterozygous for a loss-of-function mutation of FMO3 or have certain combinations of FMO3 polymorphisms may exhibit mild symptoms of the disorder [Mayatepek & Kohlmuller 1998, Zschocke et al 1999, Zschocke & Mayatepek 2000]. Transient childhood forms are a consequence of the immaturity of FMO3 expression, which is switched on after birth and continues to increase throughout childhood [Koukouritaki et al 2002]. Transient trimethylaminuria associated with menstruation. A short episode of trimethylaminuria can occur in women during menstruation [Mitchell & Smith 2001, Shimizu et al 2007]. The effect is more pronounced in women homozygous for polymorphic variants that result in a limited decrease in FMO3 enzyme activity [Shimizu et al 2007]. Precursor overload can cause a transient form of trimethylaminuria that results from saturation of the enzyme FMO3. It can occur in individuals with Huntington disease or Alzheimer disease who have been given large oral therapeutic doses of choline (≤20 g/day) [Mitchell & Smith 2001, Mitchell 2005]. Disease states Liver cirrhosis, impaired hepatocellular function, or the existence of portosystemic shunts may affect clearance of TMA absorbed from the gut. The resulting trimethylaminuria may contribute to the development of hepatic encephalopathy and coma and associated foetor hepaticus [Mitchell et al 1999]. In uremia, increased release of TMA from dietary precursors as a consequence of bacterial overgrowth in the small intestine, coupled with reduced renal clearance of TMA, can result in trimethylaminuria [Mitchell 2005]. The elevated blood concentration of TMA may contribute to nephritic neurologic conditions. Other causes of unpleasant body odor fall into two categories:Those not involving an increase of trimethylamine in the urine, including poor hygiene, gingivitis, and cases of blood-borne halitosis [Tangerman 2002] resulting from malodorous compounds other than trimethylamine. Another condition in this category is the rare metabolic disorder dimethylglycinuria, caused by dimethylglycine dehydrogenase deficiency [Binzak et al 2001]. Such conditions are distinguished by low urinary TMA and a normal urinary TMA/TMA N-oxide ratio. Those resulting in an increase of trimethylamine in the urine, including urinary tract infections, bacterial vaginosis, advanced liver or kidney disease, and cervical cancer. In these cases, the TMA/TMA N-oxide ratio is normal, but affected individuals have large amounts of TMA in the urine. In contrast, the primary genetic form of trimethylaminuria, caused by FMO3 deficiency, is characterized by a high ratio of TMA/TMA N-oxide in the urine. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with trimethylaminuria, it is recommended that the urinary ratio of TMA N-oxide to total TMA on a normal diet be determined:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with trimethylaminuria, it is recommended that the urinary ratio of TMA N-oxide to total TMA on a normal diet be determined:Ratios of 70%-89% are classified as mild.Ratios lower than 70% are classified as severe. The general rule is that the lower the ratio the more severe the disorder. Treatment of ManifestationsStrategies for the treatment of trimethylaminuria summarized below are covered in detail in Cashman et al [2003] and in "best-practice" guidelines [Chalmers et al 2006; see ]. Restriction of dietary trimethylamine and its precursors. In some cases the disorder can be successfully managed by dietary restriction of precursors of trimethylamine. This is particularly true of "mild" or moderate forms of the disorder. Affected individuals respond differently to different forms of dietary restriction; thus, urinary excretion of trimethylamine and trimethylamine N-oxide should be monitored to identify the most effective dietary regimen for an individual. Choline. One of the most important dietary sources of trimethylamine is choline. Dietary choline is absorbed through the small intestine; however, when the absorptive capacity of the small intestine is overloaded, gut bacteria metabolize choline into trimethylamine, which is readily absorbed into the blood stream. Foods rich in choline include eggs, liver, kidney, peas, beans, peanuts, soya products, and brassicas (Brussels sprouts, broccoli, cabbage, cauliflower)as well as rapeseed products such as oil and flour. Nutritionally balanced, choline-restricted diets suitable for the treatment of trimethylaminuria have been developed [Busby et al 2004]. Affected individuals should avoid lecithin (an important dietary source of choline) and lecithin-containing fish oil supplements. Trimethylamine N-oxide. Affected individuals should avoid eating seafood (fish, cephalopods, and crustaceans) because of its high content of trimethylamine N-oxide, which is reduced to trimethylamine in the human gut. Babies with trimethylaminuria who are breastfed after their mothers have eaten seafood may develop a fishy odor. Note: Freshwater fish have a lower content of trimethylamine N-oxide and thus are not a problem. Other. Milk obtained from wheat-fed cows may have significant amounts of trimethylamine and thus should be avoided. In addition to being a source of trimethylamine precursors, brassicas (Brussels sprouts, broccoli, cabbage, and cauliflower) contain indoles, which may inhibit FMO3 enzyme activity and thus increase urinary excretion of trimethylamine [Cashman et al 1999]. Intake of such vegetables should be restricted.Use of acid soaps and body lotions. Trimethylamine is a strong base (pKa 9.8). Thus, at pH 6.0, less than 0.02% of trimethylamine exists as the volatile free base. The use of soaps and body lotions with a pH close to that of normal skin (pH 5.5-6.5) helps retain secreted trimethylamine in a less volatile salt form that can be removed by washing. Sequestering of trimethylamine produced in the gut. When taken as dietary supplements, activated charcoal (750 mg 2x/day for 10 days) and copper chlorophyllin (60 mg 3x/day after meals for 3 weeks) decrease the concentration of free trimethylamine in the urine [Yamazaki et al 2004]. Suppression of intestinal production of trimethylamine. A short course of antibiotics to modulate or reduce the activity of gut microflora, and thus suppress the production of trimethylamine, is effective in some cases [Fraser-Andrews et al 2003, Chalmers et al 2006]. Such treatment may be useful when dietary restriction needs to be relaxed (e.g., for important social occasions), or when trimethylamine production appears to increase (e.g., during menstruation, infection, emotional upset, stress, or exercise). Three antibiotics with different target organisms have been used: metronidazole, amoxicillin, and neomycin. Neomycin appears to be the most effective in preventing formation of trimethylamine from choline [Chalmers et al 2006]. Laxatives, such as lactulose, to decrease intestinal transit time may also reduce the amount of trimethylamine produced in the gut.Enhancement of residual FMO3 enzyme activity. Supplements of riboflavin, a precursor of the FAD prosthetic group of FMOs, may help maximize residual FMO3 enzyme activity. Recommended intake is 30-40 mg, three to five times per day, with food. Children given riboflavin should be monitored closely because excessive amounts may cause gastrointestinal distress. Counseling. Affected individuals and their families benefit from counseling. Realization that the problem is the result of a recognized medical condition may help. As well as receiving dietary advice, affected individuals should be advised that the condition may be exacerbated during menstruation and by factors that promote sweating, such as fever, exercise, stress, and emotional upsets. Prevention of Primary ManifestationsSee Treatment of Manifestations.Prevention of Secondary ComplicationsBecause choline is essential in the fetus and in young infants for nerve and brain development, it should not be over-restricted in infants, children, and pregnant or lactating women. Large amounts of choline are transferred to the fetus via the placenta and to the newborn infant via the mother's milk, thus potentially depleting maternal choline reserves. Dietary restriction of choline increases the requirement for folate, a methyl donor.Dietary regimens should be planned and monitored to ensure that the daily intake of choline and folate meet recommendations for the age and sex of the individual [Institute of Medicine, National Academy of Sciences USA 1998; Cashman et al 2003]. For adults, adequate daily intake of choline is 550 mg for males and 425 mg for females. Agents/Circumstances to AvoidThe following should be avoided:Foods with a high content of precursors of trimethylamine or inhibitors of FMO3 enzyme activity, including seafood (fish, cephalopods, and crustaceans), eggs, offal, legumes, brassicas, and soya products; avoid or eat in moderation. Food supplements and "health" foods that contain high doses of the trimethylamine precursors choline and lecithin Drugs that are metabolized by the FMO3 enzyme; for example, the antipsychotic clozapine; the monoamine oxidase B inhibitor deprenyl; the anti-histamine ranitidine; the anti-estrogen tamoxifen; and the nonsteroidal anti-inflammatories benzydamine and sulindac [Phillips et al 2007]. These compete for residual FMO3 activity. As well as exacerbating the condition, reduced metabolism of the drug may cause adverse effects. Factors that promote sweating, such as exercise, stress, and emotional upsets Evaluation of Relatives at RiskBiochemical testing of sibs is appropriate to identify those who are affected and will benefit from early treatment of manifestations. If the causative mutations in the family have been identified, at-risk relatives can be offered molecular genetic testing.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Trimethylaminuria: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDFMO31q24.3Dimethylaniline monooxygenase [N-oxide-forming] 3FMO3 homepage - Mendelian genesFMO3Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Trimethylaminuria (View All in OMIM) View in own window 136132FLAVIN-CONTAINING MONOOXYGENASE 3; FMO3 602079TRIMETHYLAMINURIA; TMAUNormal allelic variants. FMO3 spans 27 kb and contains nine exons, of which exon 1 is non-coding [Dolphin et al 1997b]. The gene encodes a mature mRNA of 2.1 kb. Fifteen different nonsynonymous single-nucleotide variants in the gene have been identified [Phillips et al 2007]. Individually, with the exception of p.Asn61Lys and p.Leu360Pro, these have little or no effect on protein function. However, some nonsynonymous variants when present in cis configuration in the homozygous state can cause a "mild" phenotype. Pathologic allelic variants. More than 30 distinct mutations have been reported [Hernandez et al 2003] (see Table 3). Most are missense mutations, but nonsense mutations, small (1- or 2-bp) deletions and one large (12.2-kb) deletion have been reported. The most common mutations identified to date are p.Pro153Leu [Dolphin et al 1997a] and p.Glu305X [Treacy et al 1998]. Some mutations impair assembly of the holoenzyme (i.e., the ability of the apoprotein to bind FAD) whereas others affect kinetic competency [Yeung et al 2007]. Some nonsynonymous variants, when present in cis configuration (e.g., p.Glu158Lys and p.Glu308Gly) can result in a moderate decrease in enzyme activity [Koukouritaki & Hines 2005, Phillips et al 2007]. When present in the homozygous state, they may cause mild or transient trimethylaminuria, particularly in infants and young children [Zschocke et al 1999, Zschocke & Mayatepek 2000], who have low expression of FMO3 [Koukouritaki et al 2002]. The mutation p.Val187Ala does not affect enzyme activity, but a combination of p.Val187Ala with the common variant p.Glu158Lys, in cis configuration, has a severe affect on enzyme activity [Motika et al 2009]. The mutation p.Asn61Lys results in a severe reduction in FMO3 activity [Koukouritaki et al 2007] and thus is likely to cause primary genetic trimethylaminuria; however, no affected individuals with this mutation have been identified. The mutation p.Leu360Pro is the only variant to result in an increase in enzyme activity [Lattard et al 2003]. See Table 2. Table 2. Selected FMO3 Pathologic Allelic Variants View in own windowClass of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences"Mild" variants that affect enzyme activity 1 c.472G>Ap.Glu158LysNM_006894.4 NP_008825.4c.923A>Gp.Glu308Glyc.1079T>Cp.Leu360ProPathologicc.182A>Gp.Asn61Serc.458C>Tp.Pro153Leuc.[472G>A;560T>C] 2p.[Glu158Lys; Val187Ala] 2c.913G>Tp.Glu305XSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). 1. See details in paragraph preceding table.2. Denotes two changes in one alleleNormal gene product. The normal product of FMO3 is the protein flavin-containing monooxygenase 3 (FMO3), which has a molecular mass of 60 kd and contains 532 amino acid residues [Phillips et al 2007]. FMO3 is located in the membranes of the endoplasmic reticulum. The enzyme catalyzes the oxygenation of a wide range of foreign chemicals. At the site of oxygenation preferred substrates contain a soft nucleophile – typically a nitrogen, sulfur, phosphorous, or selenium atom [Krueger & Williams 2005]. One of the reactions catalyzed by FMO3 is the oxygenation of the odorous tertiary amine trimethylamine to its non-odorous N-oxide. Abnormal gene product. The mutations that cause severe trimethylaminuria essentially abolish FMO3 activity and are thus "null" mutations [Phillips et al 2007]. The mutation p.Asn61Ser, however, abolishes N-oxygenation of trimethylamine and thus causes trimethylaminuria but has no effect on the S-oxygenation of methimazole [Dolphin et al 2000].